Abstract
The effects of asbestos fibers on human immune cells have not been well documented. We have developed a continuously exposed cell line model using the human T-lymphotropic virus 1 (HTLV-1)-immortalized human T cell line MT-2. Sublines continuously exposed to chrysotile (CH) or crocidolite (CR) showed acquired resistance to asbestos-induced apoptosis following transient and high-dose re-exposure with fibers. These sublines in addition to other immune cells such as natural killer cells or cytotoxic T lymphocytes exposed to asbestos showed a reduction in anti-tumor immunity. In this study, the expression of genes and molecules related to antioxidative stress was examined. Furthermore, complexes related to oxidative phosphorylation were investigated since the production of reactive oxygen species (ROS) is important when considering the effects of asbestos in carcinogenesis and the mechanisms involved in resistance to asbestos-induced apoptosis. In sublines continuously exposed to CH or CR, the expression of thioredoxin decreased. Interestingly, nicotinamide nucleotide transhydrogenase (NNT) expression was markedly enhanced. Thus, knockdown of NNT was then performed. Although the knockdown clones did not show any changes in proliferation or occurrence of apoptosis, these clones showed recovery of ROS production with returning NADPH/NADP+ ratio that increased with decreased production of ROS in continuously exposed sublines. These results indicated that NNT is a key factor in preventing ROS-induced cytotoxicity in T cells continuously exposed to asbestos. Considering that these sublines showed a reduction in anti-tumor immunity, modification of NNT may contribute to recovery of the anti-tumor effects in asbestos-exposed T cells.
Highlights
Exposure to asbestos fibers can cause asbestosis, a typical form of pneumoconiosis, and which is characterized as lung fibrosis (Wolff et al, 2015; Furuya et al, 2018)
Environment International 138 (2020) 105654 contaminated iron content and other elements (Kohyama et al, 1996), and CH-A is mined and obtained from Zimbabwe while CH-B is from Canada) or to CR at relatively low doses (Hyodoh et al, 2005; Miura et al, 2006; Maeda et al, 2012). We found that these sublines showed similar cellular and molecular alterations such as production of cytokines characterized by over-production of interleukin (IL)-10 and transforming growth factor (TGF)-β, and reduced production of interferon (IFN)-γ and tumor necrosis factor (TNF)-α (Hyodoh et al, 2005; Miura et al, 2006; Maeda et al, 2012)
Proteins were extracted from MT-2Org and fiber-removed CB1 lines exposed to 50 μg/ml CH fibers for two days, and MT-2Org and fiber-removed CR1 lines exposed to 100 μg/ml CR fibers for two days
Summary
Exposure to asbestos fibers can cause asbestosis, a typical form of pneumoconiosis, and which is characterized as lung fibrosis (Wolff et al, 2015; Furuya et al, 2018). Asbestos can cause lung cancers, malignant mesothelioma (MM) and other cancers (Lazarus et al, 2012; Stayner et al, 2013; Prazakova et al, 2014). The most important factor pertaining to asbestos carcinogenesis is iron (Kamp, 2009; Toyokuni, 2019). The iron generates reactive oxygen species (ROS) and reactive nitrogen species (RNS) via Fenton’s reaction at inhaled and remaining sites such as the lung, pleural cavity and regional lymph nodes (Kamp, 2009; Toyokuni, 2019). Regarding T helper (Th) cells, we have utilized the human T-lymphotropic virus 1 (HTLV-1)-immortalized human T cell line MT-2 (MT2Org) to establish a model based on continuous and relatively low-dose exposure (Miura et al, 2006). We established several independent sublines of cells exposed continuously to CH-A or CH-B
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